This invention relates to contrast agents and more particularly to contrast agents for use in magnetic resonance imaging.
Magnetic resonance imaging (MRI) works on the principle that when an external magnetic field is applied across tissue the atoms in the tissue align themselves in the direction of the applied field. The atoms may be thought of as behaving as tiny magnets. When radio frequency (RF) electromagnetic radiation is applied across the tissue, the atoms, acting as magnets, tilt out of alignment with the external field as they absorb energy from the RF field. When the RF field is removed the atoms slowly regain their alignment with the applied external field. The time taken by the atoms to regain their alignment after perturbation by the RF field is called the relaxation time. See, xe2x80x9cMagnetic Resonance Imaging: Principles and Applications,xe2x80x9d Eds. Kean, D. M. and Smith, M. A., Williams and Wilkins, Baltimore Md. and xe2x80x9cMagnetic Resonance Imaging: Basic Principles,xe2x80x9d Second Edition, Young, Stuart W., Raven Press, New York (1984). As the atoms regain their alignment with the external field, they emit a radio frequency signal from which images can be constructed.
As those skilled in the art of magnetic resonance imaging recognize, there are two types of spin relaxation referred to as T1 and T2. These relaxation times are illustrated in FIGS. 1 and 2. FIG. 1 shows the reorientation of dipoles into alignment with an external magnetic field at the end of an RF pulse. An RF pulse will also cause an atom to precess at what is known as the Larmor frequency and this precession is shown in FIG. 2.
The atoms in water molecules are often utilized to generate magnetic resonance images of human subjects. Biological tissue contains two forms of water molecules, namely, those that are free (free water) and those that are bound to proteins and other tissue components by hydrogen bonding and other electrostatic interactions (bound water). MRI technique utilizes the difference in the relaxation times of free water and bound water to establish contrast. The relaxation time T1 of free water is on the order of 3 seconds at 0.1 Tesla while that of bound water is typically less than a second. Thus, the larger the portion of bound water in a particular tissue the lower the resulting T1. In order to carry out imaging in a realistic time frame, the T1 relaxation time of water (both bound and unbound) must be lowered significantly. The lowering of the T1 relaxation time is very important in order that a large sample set of values may be acquired in a sufficiently short period of time so that the required mathematical transformations necessary to create an image may be performed.
MRI contrast agents have been developed to lower the tissue relaxation parameters T1 and T2. Currently, the diminution in relaxation times is achieved by the introduction of a paramagnetic species such as a transition metal complex into the tissue site of interest before imaging. Paramagnetic agents have positive magnetic susceptibility so that the local magnetic field induced by such contrast agents in the presence of an external magnetic field is additive to that field. Paramagnetic contrast agents that have received wide attention are first row transition metals, lanthanides and free radicals. Because of the toxicity of both transition metals and lanthanides, these metals are complexed with chelates to reduce their toxicity. Gadolinium (Gd) and manganese (Mn) complexed with DTPA are the most commonly used contrast agents in magnetic resonance imaging. Paramagnetic and ferromagnetic particles have also been evaluated for reticuloendothelial tissue imaging such as for imaging the liver. Not only are gadolinium and other transition metal complexes toxic at high doses, they cannot be modified to introduce targeting agents such as antibodies without first being encapsulated in a secondary carrier. The present inventors have discovered an entirely new class of contrast agents for MRI.
The contrast agents of the invention are electroactive materials having regions or moieties of high electron density or charge, or that exhibit other electroactive properties, and which may be conducting or nonconducting. The use of the contrast agents of the invention reduce relaxation times, thereby facilitating image creation. Preferred contrast agents for use in the present invention include electroactive polymers, inorganic clusters, carbon clusters, or molecules that inherently exhibit donor-acceptor behavior. Examples of particularly preferred contrast agents include, but are not limited to polypyrrole, poly(p-phenylene), poly(p-phenylene-vinylene), poly(thiophene), poly(aniline) and poly(porphyrin), poly(heme), Ag-TCNQ, Ag-TDCN, C60-TCNQ, C50-TCNQ, Ag-TTF, C50-TTF, C60-TTF, C60, C70, or formulations of fullerenes such as C60 or C70 with existing contrast agents such as Gd or Mn, wherein TCNQ represents 7,7,8,8-Tetracyanoquinodimethane, and TTF represents Tetrathiafulvalene.
In preferred embodiments, the contrast agents of the present invention may be prepared as formulations of solid or porous particulates, such as colloids or microspheres, as a micelle, as an aerogel, or may also be encapsulated, for example in a liposome. It is also preferred that the contrast agents and their formulations be cytocompatible and biocompatible. It is particularly preferred that the contrast agents of the invention be produced with particle sizes in the range of 5 nanometers to 4 micrometers. Moreover, the particles are preferably formed as a colloidal suspension, wherein the contrast agent concentration is in the range of 1 microgram per ml to 0.5 grams per ml.
In another aspect, the invention includes modification of the surface of the contrast agent particles to bear molecules that bind to specific cell types via receptors or similar agents to achieve targeted imaging. In addition, in one particularly preferred embodiment, the particles can be surface-modified with alkylene oxides to achieved increased circulation times within a subject.
In yet another aspect, the invention provides a method for decreasing relaxation times in magnetic resonance imaging comprising introducing into a subject an electroactive material. Preferably, the electroactive materials comprise an electroactive polymer, an inorganic cluster, carbon cluster or a molecule that inherently exhibits electron donor-acceptor behavior. A magnetic resonance imaging system is also provided and includes a magnetic resonance imaging apparatus for generating images of a subject and a contrast agent of the present invention. An apparatus is provided for introducing the contrast agent into the subject.